Effects of Inhibitors of FGFR3 on Gene Transcription

Abstract

Methods of utilizing biomarkers to identify patients for treatment or to monitor response to treatment are taught herein. Alterations in levels of gene expression of the biomarkers, particularly in response to FGFR3 inhibition, are measured and identifications or adjustments may be made accordingly.

1 . A method of identifying a patient for treatment, the method comprising:
 administering an amount of an inhibitor of FGFR3 to the patient, and   testing a sample obtained from the patient after the administration of the inhibitor to measure gene expression of at least one biomarker selected from Table I,   wherein detection of an alteration in level of expression compared to baseline of the at least one biomarker is indicative of the candidacy of the patient for treatment.   
     
     
         2 . A method of identifying a patient for treatment, the method comprising:
 testing a sample obtained from a patient to measure gene expression of at least one biomarker selected from Table I,   wherein detection of the presence of gene expression of the at least one biomarker is indicative of the candidacy of the patient for treatment.   
     
     
         3 . A method of monitoring response of a patient in need thereof to treatment for a cell proliferative disorder, the method comprising:
 administering an amount of an inhibitor of FGFR3 to the patient,   testing a sample obtained from the patient after the administration of the inhibitor to measure gene expression of at least one biomarker selected from Table I,   wherein detection of an alteration in level of expression of the at least one biomarker is compared to baseline is indicative of a favorable response of the patient to the treatment.   
     
     
         4 . A method of monitoring response of a patient to treatment by an inhibitor of FGFR3 for a cell proliferative disorder, the method comprising:
 testing a sample obtained from the patient to measure gene expression of at least one biomarker selected from Table I,   wherein detection of an alteration in level of expression of the at least one biomarker compared to baseline is indicative of a favorable response of the patient to the treatment.   
     
     
         5 . A method of utilizing a biomarker in treatment of a cell proliferative disorder in a patient, the method comprising
 administering an amount of an inhibitor of FGFR3 to the patient,   testing a sample obtained from the patient to measure gene expression of at least one biomarker selected from Table I, and   subsequently administering the same or a different inhibitor of FGFR3 to the patient provided favorable alteration of the level of expression of the at least one biomarker is detected upon administration of the initial inhibitor.   
     
     
         6 . A method of treating a multiple myeloma patient, the method comprising administering a therapeutically effective amount of an agent that alters the level of expression compared to baseline of a biomarker identified in Table I, thereby inhibiting abnormalities associated with multiple myeloma. 
     
     
         7 . A method of adjusting a dosage amount of an inhibitor of FGFR3 for treatment of a cell proliferative disorder in a patient, the method comprising:
 administering an initial amount of the inhibitor of FGFR3 to the patient,   monitoring gene expression of at least one biomarker selected from Table I after the administration of the initial amount of the inhibitor, and   adjusting the amount for subsequent administration of the inhibitor to the patient based upon the level of alteration of the expression of the biomarker or biomarkers that has occurred upon administration of the initial amount.   
     
     
         8 . A method of utilizing a biomarker to identify an FGFR3 inhibitory compound for potential treatment of multiple myeloma or to guide a decision to progress an FGFR3 inhibitory compound to further development for treatment of multiple myeloma, the method comprising:
 contacting the compound with a KMS18 or KMS11 cell culture, and   testing a portion of the cell culture to measure gene expression of at least one biomarker selected from Table I,   wherein detection of an alteration in expression of the at least one biomarker is indicative of an identification of the compound for treatment or a favorable decision to progress the compound for further development.   
     
     
         9 . A method of selecting an appropriate inhibitor of FGFR3 to administer to a patient in need of treatment with said inhibitor, the method comprising:
 administering an initial inhibitor of FGFR3 to the patient,   testing a sample obtained from the patient to measure gene expression of at least one biomarker selected from Table I, and   subsequently administering the initial inhibitor of FGFR3 to the patient provided favorable alteration of the level of expression of the at least one biomarker is detected upon administration of the initial inhibitor.   
     
     
         10 . A method of utilizing a biomarker to identify an FGFR3 inhibitory compound for potential treatment of a cell proliferative disorder, the method comprising:
 contacting the compound with a cell line or tissue associated with the disorder, and   testing a portion of the cell culture or tissue after the contacting to measure gene expression of at least one biomarker that has been altered compared to baseline,   wherein detection of an alteration in expression of the at least one biomarker is indicative of an identification of the compound for treatment.   
     
     
         11 . The method of  claim 1 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table II is indicative of the candidacy of the patient for treatment. 
     
     
         12 . The method of  claim 1 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table III is indicative of the candidacy of the patient for treatment. 
     
     
         13 . The method of  claim 1 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table IV is indicative of the candidacy of the patient for treatment. 
     
     
         14 . The method of  claim 1 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table V is indicative of the candidacy of the patient for treatment. 
     
     
         15 . The method of  claim 1 , wherein detection of an alteration in level of expression compared to baseline of at least two biomarkers selected from a subset of Table I represented by Table II is indicative of the candidacy of the patient for treatment. 
     
     
         16 . The method of  claim 1 , wherein the measurement of gene expression is made by detecting the quantity of RNA transcribed by the biomarker. 
     
     
         17 . The method of  claim 1 , wherein the measurement of gene expression is made by detecting the quantity of DNA produced from reverse transcription of an RNA transcribed by the biomarker. 
     
     
         18 . The method of  claim 1 , wherein the measurement of gene expression is made by detecting a polypeptide or protein encoded by the biomarker. 
     
     
         19 . The method of  claim 1 , wherein the at least one biomarker is operably linked to a gene chip. 
     
     
         20 . The method of  claim 1 , wherein the at least one biomarker is represented in computer readable format. 
     
     
         21 . The method of  claim 1 , wherein the testing comprises contacting the sample with a gene chip comprising the biomarkers of any one of Tables I through V. 
     
     
         22 . The method of  claim 1 , wherein the detecting step comprises comparing the gene expression level of the biomarker with a gene database. 
     
     
         23 . The method of  claim 1 , wherein the treatment comprises administration of a therapeutically effective amount of the same or a different inhibitor of FGFR3 to the patient. 
     
     
         24 . The method of  claim 1 , wherein the treatment is for a cell proliferative disorder. 
     
     
         25 . The method of  claim 1 , wherein the treatment is for a neoplastic disease. 
     
     
         26 . The method of  claim 1 , wherein the treatment is for multiple myeloma. 
     
     
         27 . The method of  claim 1 , wherein the treatment is for t(4; 14) multiple myeloma. 
     
     
         28 . The method of  claim 1 , wherein the inhibitor is selected from the group consisting of CHIR-258, SU-5402, and PD-173074. 
     
     
         29 . The method of  claim 1 , wherein the inhibitor is CHIR-258. 
     
     
         30 . The method of  claim 1 , wherein the biomarker is selected from the group consisting of CCL3, LOC150271, CD48, DUSP4, and ITGB7. 
     
     
         31 . The method of  claim 1 , wherein the biomarker is selected from the group consisting of LOC150271, CD48, DUSP4, and ITGB7. 
     
     
         32 . The method of  claim 1 , wherein the biomarker is CCL3. 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 1 , further comprising establishing a baseline level for the patient prior to administering the FGFR3 inhibitor. 
     
     
         35 . The method of  claim 3 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table II is indicative of a favorable response of the patient to the treatment. 
     
     
         36 . The method of  claim 3 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table III is indicative of a favorable response of the patient to the treatment. 
     
     
         37 . The method of  claim 3 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table IV is indicative of a favorable response of the patient to the treatment. 
     
     
         38 . The method of  claim 3 , wherein detection of an alteration in level of expression compared to baseline of at least one biomarker selected from a subset of Table I represented by Table V is indicative of a favorable response of the patient to treatment. 
     
     
         39 . The method of  claim 3 , wherein detection of an alteration in level of expression compared to baseline of at least two biomarkers selected from a subset of Table I represented by Table II is indicative of a favorable response of the patient to the treatment. 
     
     
         40 . The method of  claim 3 , wherein the administering step is repeated before the step of testing a sample obtained from the patient. 
     
     
         41 . The method of  claim 3 , wherein the inhibitor of FGFR3 is administered in a therapeutically effective amount. 
     
     
         42 . The method of  claim 5 , wherein favorable alteration of the level of expression comprises alteration compared to baseline of at least one biomarker selected from a subset of Table I represented by Table II. 
     
     
         43 . The method of  claim 5 , wherein favorable alteration of the level of expression comprises alteration compared to baseline of at least one biomarker selected from a subset of Table I represented by Table III. 
     
     
         44 . The method of  claim 5 , wherein favorable alteration of the level of expression comprises alteration compared to baseline of at least one biomarker selected from a subset of Table I represented by Table IV. 
     
     
         45 . The method of  claim 5 , wherein favorable alteration of the level of expression comprises alteration compared to baseline of at least one biomarker selected from a subset of Table I represented by Table V. 
     
     
         46 . The method of  claim 5 , wherein favorable alteration of the level of expression comprises alteration compared to baseline of at least two biomarkers selected from a subset of Table I represented by Table II. 
     
     
         47 . The method of  claim 5 , wherein the initial inhibitor and the subsequently administered inhibitor are each selected from the group consisting of CHIR-258, SU-5402, and PD-173074. 
     
     
         48 . The method of  claim 5 , wherein the initial inhibitor is CHIR-258. 
     
     
         49 . The method of  claim 5 , wherein the subsequently administered inhibitor is CHIR-258. 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 6 , wherein the alteration compared to baseline of at least one biomarker is selected from a subset of Table I represented by Table II. 
     
     
         52 . The method of  claim 6 , wherein the alteration compared to baseline is of at least one biomarker selected from a subset of Table I represented by Table III. 
     
     
         53 . The method of  claim 6 , wherein the alteration compared to baseline is of at least one biomarker selected from a subset of Table I represented by Table IV. 
     
     
         54 . The method of  claim 6 , wherein the alteration compared to baseline is of at least one biomarker selected from a subset of Table I represented by Table V. 
     
     
         55 . The method of  claim 6 , wherein the alteration compared to baseline of at least two biomarkers selected from a subset of Table I represented by Table II. 
     
     
         56 . The method of  claim 6 , wherein the agent is CHIR-258. 
     
     
         57 . The method of  claim 6 , wherein the patient is a t(4:14) multiple myeloma patient. 
     
     
         58 . The method of  claim 7 , wherein the gene expression is monitored for at least one biomarker selected from a subset of Table I represented by Table II. 
     
     
         59 . The method of  claim 7 , wherein the gene expression is monitored for at least one biomarker selected from a subset of Table I represented by Table III. 
     
     
         60 . The method of  claim 7 , wherein the gene expression is monitored for at least one biomarker selected from a subset of Table I represented by Table IV. 
     
     
         61 . The method of  claim 7 , wherein the gene expression is monitored for at least one biomarker selected from a subset of Table I represented by Table V. 
     
     
         62 . The method of  claim 7 , wherein the monitoring comprises contacting the sample with a gene chip comprising the biomarkers of any one of Tables I through V and comparing the gene expression level of the biomarker with a gene database. 
     
     
         63 . The method of  claim 10 , wherein the biomarker is selected from Table I. 
     
     
         64 . A method of identifying a patient for treatment, the method comprising:
 administering an amount of an inhibitor of FGFR3 to the patient, and   testing a sample obtained from the patient after the administration of the inhibitor to measure gene expression of at least one biomarker selected from the group consisting of CCL3, DUSP6, ANXA9, CR2, AL531683, ZNF589, AW274468, FRMD3, LTB, and WDR42A,   wherein detection of an alteration in level of expression compared to baseline of the at least one biomarker is indicative of the candidacy of the patient for treatment.   
     
     
         65 . A method of monitoring response of a patient to treatment by an inhibitor of FGFR3 for a cell proliferative disorder, the method comprising:
 testing a sample obtained from the patient to measure gene expression of at least one biomarker selected from the group consisting of CCL3, DUSP6, ANXA9, CR2, AL531683, ZNF589, AW274468, FRMD3, LTB, and WDR42A,   wherein detection of an alteration in level of expression of the at least one biomarker compared to baseline is indicative of a favorable response of the patient to the treatment.   
     
     
         66 . The method of  claim 1 , wherein the biomarker is not any or all of CCL3, DUSP6, ANXA9, CR2, AL531683, ZNF589, AW274468, FRMD3, LTB, and WDR42A.